The effect of tolbutamide on mechanical performance and energy metabolism of the diabetic heart perfused with Krebs Henseleit buffer containing an appropriate substrate will be examined. The response of these hearts to varying degrees of preload will be measured and comparisons made between the tolbutamide-treated and untreated diabetic and nondiabetic groups. The hearts will also be examined for metabolic changes mediated by tolbutamide. We have found that short-term tolbutamide treatment protects the nondiabetic, ischemicmyocardium against damage. Associated with this protection is a stimulation in glycolytic flux, enhanced ATP synthesis and an elevation in tissue high energy phosphate levels. To further clarify the site of tolbutamide action, studies will be performed to examine the effect of the sulfonylurea on pyruvate dehydrogenase activity and pyruvate utilization by the ischemic myocardium. We will also examine the effect of tolbutamide on the metabolism and mechanical recoverability of the diabetic, ischemic myocardium. Standard glycolytic flux, lactate and pyruvate production and oxygen consumption studies will be performed. The measurement of key metabolic intermediates will be employed to establish the mode of tolbutamide action. The basis for the toxic effects of high tolbutamide levels will also be investigated.